Carbinoxamine tannate

ABSTRACT

The invention pertains to carbinoxamine tannate and to a method for preparing carbinoxamine tannate by reacting carbinoxamine free base at a temperature of about 50 to about 150° C. with tannic acid neat or as an aqueous slurry containing about 5 to about 30 wt. % water.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation-in-part of pending U.S. patentapplication Ser. No. 10/017,131 filed Dec. 14, 2001.

FIELD OF THE INVENTION

[0002] The invention pertains to carbinoxamine tannate, its method ofpreparation and to pharmaceutical compositions containing carbinoxaminetannate.

BACKGROUND OF THE INVENTION

[0003] Carbinoxamine, i.e.,2-[(4-chlorophenyl)-2-pyridinylmethoxy]-N,N-dimethyl-ethanamine, is awell-known antihistamine. The compound has the molecular formulaC₁₆H₁₉ClN₂O, a molecular weight of 290.79 and is a liquid having aboiling point (0.1 mm Hg) of 158-162° C. The 1-form has a boiling point(0.5 mm Hg) of 143-144° C., a density (at 20° C.) of 1.5522 and anoptical rotation of [α]_(D) ²⁵−6.8° (c=2 in methanol, while thed-tartrate salt of the 1-form has a melting point of 143-144.5° C. andan optical rotation of [α]_(D) ²⁵+37.2° (c=20 in methanol. Sincecarbinoxamine is insoluble in water, it typically is administered in theform of the hydrochloride, maleate or tartrate salt which is freelysoluble in water. It is most often administered in the form of itsmaleate salt which has a melting point of 117-119° C. It is typicallyadministered to human beings in need of such medication in the form of asyrup, tablet and/or suspension. It frequently is administered incombination with one or more other antihistamine and/or antitussivecompositions, e.g., diphenhydramine hydrochloride, chlorpheniraminemaleate, dextromethorphan hydrobromide monohydrate, etc.

[0004] The currently administered forms of carbinoxamine, i.e.,generally an acid salt such as the hydrochloride, maleate or tartrateare disadvantageous in that they are absorbed very quickly in themammalian body. Accordingly, although such forms provide prompt relief,multiple doses must be taken on a daily basis to provide an effectivelevel of medicament over the prescribed period of treatment (generallyseveral days to one week). It would be very desirable if a form of wasavailable that would have extended-release properties, i.e., thecarbinoxamine would be slowly released into the patient's bloodstreamover a prolonged period of time. Until recently, the only slow-releaseforms of carbinoxamine that were available were those such aspolymer-coated tablets. Such prior art formulations provided mixedresults in that the carbinoxamine was not available for adsorption intothe patient's bloodstream until the polymeric coating was dissolved, butthereafter the carbinoxamine was quickly absorbed and metabolized. Theresult is that frequently, the carbinoxamine had to again beadministered to the patient within the period of only a few hours.

[0005] The foregoing problem was solved by converting the carbinoxaminefree base into its tannate salt by reaction of the free base with tannicacid. The tannate salt stabilizes the carbinoxamine free base and mostimportantly, imparts extended release properties to the carbinoxamine.In recent years, tannate salts of antihistamines have become known,e.g., see U.S. Pat. Nos. 5,599,846; 5,663,415; 6,037,358, 6,287,597, and6,306,904.

[0006] Tannic acid is commercially available and is used in manyindustrial applications. It is frequently referred to as gallotannicacid, gallotanin; glycerite or tannin. It is a pale tan powder having adecomposition point of 210-215° C., and is highly soluble in water andalcohols. Its molecular formula is C₇₆H₅₂O₄₆ and its CAS number is1401-55-4. Tannic acid is typically produced from Turkish or Chinesenutgall and has a complex non-uniform chemistry and typically containsabout 5-10 wt. % water.

[0007] Commercially available antihistamine tannate compositions arerelatively impure. Such compositions are typically prepared by reactingthe antihistamine free base with tannic acid in the presence of avolatile solvent, usually isopropanol. The yield is only fair (e.g.about 70%) and decomposition products e.g. 2-5 wt. %, and a significantamount of the volatile solvent, e.g. 6-10 wt. %, based on the weight ofthe composition, remains with the product and cannot be removed.

[0008] Typically, in the conventional isopropanol route, theantihistamine free base and the tannic acid will be present in theisopropanol at a concentration of about 20wt. %, based on the weight ofthe reaction mixture. The reaction mixture is stirred for about onehour, while maintaining a temperature of 60-70° C. The reaction mixtureis cooled to room temperature and filtered. The precipitate is vacuumdried for an extended period of time at a temperature of 60-80° C. Ayield of product of only about 70% is obtained and the product puritywill be about 85-90 wt. %, based on the weight of the composition (theimpurities consist of isopropanol and decomposition products whichcannot be removed).

[0009] Many antihistamine tannates are heat sensitive and thereforeundergo decomposition quite readily upon prolonged exposures totemperatures as low as 50° C. Accordingly, even when the solventutilized in its preparation has a relatively high vapor pressure such asis in the case of isopropanol, it is impossible to reduce the solventcontent below about 6 wt. %, based on the weight of the antihistaminetannate composition, even at reduced pressures and very mild elevatedtemperatures. Moreover, from an environmental point, it would be mostdesirable if the antihistamine tannate could be prepared such that theuse of volatile solvents could be avoided.

[0010] The process disclosed in U.S. Pat. No. 5,663,415 represents asignificant improvement over the isopropanol route. The processdisclosed in the '415 patent involves three steps:

[0011] (a) the antihistamine in the form of its free base is contactedwith tannic acid in the presence of water at a maximum temperature whichwill not cause decomposition of the antihistamine tannate to an extentof greater than about 5 wt %, based on the weight of the antihistaminetannate,

[0012] (b) the antihistamine is allowed to remain in contact with thetannic acid in the presence of water for a period of time of about 5minutes to 4 hours at said maximum temperature; and

[0013] (c) the antihistamine tannate resulting from step (b) isfreeze-dried at a temperature and at a reduced pressure and for suchperiod of time that (i) at least about 90 wt. % of the water is removedfrom the antihistamine tannate and (ii) decomposition of theantihistamine tannate will be limited to a maximum of about 5 wt. %.

[0014] The '415 patent discloses a three-step method that results in theproduction of pure antihistamine tannate compositions having a minimumpurity level of at least 90 wt. %, usually at least 95 wt. % and oftenat least 98 wt. %, based on the weight of the composition, with a yieldof at least about 90% and often with a yield in excess of 97%. The chief“impurity” present in the compositions prepared by the process of the'415 patent is water which is present in an amount of 1-5 wt. %, basedon the weight of the composition. However, the '415 patent does notdisclose carbinoxamine tannate.

[0015] Although the process disclosed in the '415 patent represents adramatic improvement leading to very pure antihistamine tannatecompositions, it has several drawbacks: freeze-drying is quitetime-consuming (typically 30-36hours to remove 1 liter of water) andexpensive and requires specialized equipment in order to achieve thereduced pressures and temperature required to dry the antihistaminetannate composition, i.e., a pressure of not greater than about 500milliTorr and a temperature in the range of about −60° C. to −20° C.Such specialized equipment also limits the amount of product that can beprocessed within a reasonable amount of time.

[0016] It has now been found that by the process of this invention, itis possible, to convert carbinoxamine into carbinoxamine tannate andunexpectedly, the carbinoxamine does not undergo racemization in thecourse of its conversion to the tannate. This was quite surprising sincea similarly useful antihistamine, e.g., levo-phenylephrine, undergoesracemization when it is reacted with tannic acid by the hot melt processof the invention to produce the tannate salt.

DETAILED DESCRIPTION OF THE INVENTION

[0017] In accordance with the process of the invention, carbinoxaminetannate is prepared by reacting carbinoxamine free base with tannicacid. If the carbinoxamine is present in the form of a salt (typically amaleate), the salt is neutralized with a stoichiometric amount of a basesuch as aqueous sodium or potassium hydroxide (e.g., 10 wt %concentration) and the resulting carbinoxamine layer is washed free ofsalts. The carbinoxamine free base is heated to a temperature of about50 to about 150° C., preferably 70 to 120° C., and tannic acid is slowlyadded, while mixing, to the carbinoxamine free base over a period of afew minutes to about one hour. The reaction mixture is continuouslystirred while maintaining such temperature range for a period of about10 minutes to about 2 hours. Thereafter, the reaction mixture is cooledto room temperature. If the process is carried out with the tannic acidutilized neat, the resultant product need not be dried (it will,however, contain 1-3 weight percent of water since the tannic acid ascommercially available contains 5-10 wt. % water). After any desireddrying, the product is preferably milled to form a free-flowing powderpreferably to a particle size of about 50 to about 200 mesh.

[0018] As mentioned above, the tannic acid may be utilized neat, i.e.,no additional diluent or solvent is employed during the reaction.However, the reaction mixture without any added water is very viscous.Therefore, water, e.g. 5-30 wt. %, may be added to facilitate thestirring of the reaction mass. If desired, any such added water mayultimately be removed from the reaction product in a separate step bywell-known processes, e.g. drying under vacuum (about 1 mm Hg) at about65 to about 75° C. for 1-10 hours or more, sparging with nitrogen for 1to 10hours or more, etc.

[0019] The molar ratio of the carbinoxamine free base to the tannic acidis generally in the range of about 4 to about 8, preferably 5 to 6,moles of carbinoxamine free base per mole of tannic acid.

[0020] The carbinoxamine tannate prepared by the process of theinvention will have a softening point which is inversely related to themoisture content (as determined by Karl Fischer analysis) as may be seenfrom the following table: Softening Point, Moisture Content, ° C. %(K.F.) 58-63 8.7 69-74 5.5 78-83 2.6 125-130 0.9

[0021] The carbinoxamine tannate prepared by the process of theinvention may be prepared for administration in the form ofpharmaceutically acceptable compositions such as powders, capsules,elixirs, syrups, nasal sprays, etc.

[0022] Tablets containing the carbinoxamine tannate may be prepared in aconventional manner by the addition of suitable pharmaceutical carriers,including fillers, diluents, lubricants and the like as well asconventional and well known binding and disintegrating agents. Atypicaltablet composition of the present invention will contain, in addition tothe phenylephrine tannate, microcrystalline cellulose, corn starch,magnesium stearate, croscarmellose sodium and coloring matter.

[0023] The suspension formulations of the carbinoxamine tannate willtypically additionally contain citric acid, caramel, glycerin, sorbitolsolution, propylene glycol, saccharin sodium, sodium benzoate, flavoringagent and purified water.

[0024] If desired, the carbinoxamine tannate prepared by the process ofthe invention may be formulated with other pharmaceutically activeingredients such as expectorants, antihistamines and antitussives, e.g.,dextromethorphan, chlorpheniramine, dextrochlorpheniramine,brompheniramine, dextrobrompheniramine, pyrilamine, phenylephrine,ephedrine, carbetapentane, guaifenesin, and the like. Typically, theseother active ingredients may be employed in the form of their free basesor as their salts, e.g., citrates, maleates, hydrobromides,hydrochlorides, tannates, etc.

[0025] The following nonlimiting examples shall serve to illustrate thepresent invention. Unless otherwise indicated, all parts and percentagesare on a weight basis.

EXAMPLE 1

[0026] Carbinoxamine free base was prepared from commercially availablecarbinoxamine maleate as follows.

[0027] Carbinoxamine maleate in the amount of 300 g (1.03 moles) wasplaced in a 2 liter flask and thereafter 640 g of a 10% aqueous solutionof sodium hydroxide were charged to the flask with stirring. Thereaction mixture was heated to a temperature of 45-55° C. with stirringfor about 30 minutes. Thereafter, stirring was discontinued and thereaction mixture was allowed to settle. The upper organic layer wasseparated and mixed, with stirring, with 300 g of water and heated to atemperature of 70-75° C. for several minutes. The mixture was thenallowed to settle and the lower organic layer was recovered. The yieldof the carbinoxamine free base was 225 g (96.5% of theory on ananhydrous basis).

EXAMPLE 2

[0028] Carbinoxamine tannate was prepared from the carbinoxamine freebase prepared in Example 1 and tannic acid as follows.

[0029] Water in the amount of 12 g was charged to a 500 ml beaker andheated to 75-85° C. 78.4 g of carbinoxamine free base (K.F. moisturecontent of 7.8%) was added with stirring while maintaining thetemperature of 75-85° C. Thereafter, 89.1 g of tannic acid (K.F.moisture content of 4.8%) were charged to the beaker over a period ofabout 30 minutes, with stirring, while maintaining a temperature of75-85° C. A uniformly viscous slurry resulted and this slurry was thenpoured into a glass dish and allowed to cool to room temperature. Thereaction product was then pulverized and the powder was determined tohave a K.F. moisture content of 8.7% and a softening point of 58-63° C.

[0030] A portion of the reaction product was dried in a vacuum oven anddried at 50° C. to a K.F. moisture content of 2.6%; the dried producthad a softening point of 78-83° C. The base assay was 44.2% as is (45.4%on an anhydrous basis). The reaction product was subjected to HPLCanalysis which indicated no significant level of impurity.

[0031] The reaction product was vacuum dried to a K.F. moisture contentof 0.9%; such dried product had a softening point of 125-130° C. A 2 galiquot sample of such dried product was mixed with 110 g of methylenedichloride, stirred for 10 minutes and then filtered. The filtrate wasevaporated to dryness and 0.0178 g of methylene dichloride-solublematerial was obtained. The weight of the methylene dichloride-insolublecarbinoxamine tannate product was 2.0061 g. Based on the followingequation, a reaction completion of 99.11% was obtained: 100−100(0.0178/2.0061)=99.11%

What is claimed is:
 1. A composition comprising carbinoxamine tannate.2. A therapeutic antihistamine composition comprising a pharmaceuticallyeffective amount of an active ingredient comprising carbinoxaminetannate.
 3. A therapeutic composition as claimed in claim 2 in tabletform.
 4. A therapeutic composition as claimed in claim 2 in suspensionform.
 5. A therapeutic composition as claimed in claim 2 in syrup form6. A therapeutic composition as claimed in claim 2 further comprisingone or more antitussive, expectorant and/or antihistamine compositions.7. The composition of claim 6 wherein the antitussive, expectorantand/or antihistamine compositions are selected from the group consistingof dextromethorphan, guaifenesin, chlorpheniramine,dextrochlorpheniramine, brompheniramine, pyrilamine, phenylephrine,ephedrine, pseudoephedrine and carbetapentane.
 8. A method forsuppressing the production of histamines in a human being whichcomprises orally administering to such human being a therapeutic amountof a composition comprising an active ingredient comprisingcarbinoxamine tannate.
 9. A method as claimed in claim 8 wherein saidcomposition is in tablet form.
 10. A method as claimed in claim 8wherein said composition is in suspension form.
 11. A method as claimedin claim 8 wherein said composition is in syrup form.
 12. A method forpreparing carbinoxamine tannate comprising reacting carbinoxamine freebase with tannic acid at a temperature of about 50 to about 150° C. andthereafter recovering the resultant carbinoxamine tannate.
 13. Themethod of claim 12 wherein the reaction is carried out at a temperatureof 70 to 120° C.
 14. The method of claim 12 wherein the carbinoxaminefree base is employed in an amount of about 4 to about 8 moles of thefree base per mole of tannic acid.
 15. The method of claim 14 whereinthe carbinoxamine free base is employed in an amount of 5 to 6 moles ofthe free base per mole of tannic acid.
 16. The method of claim 12wherein the reaction is carried out in the additional presence of about5 to about 30 wt. % water.
 17. The method of claim 12 wherein therecovered carbinoxamine tannate is subsequently died under vacuum at atemperature of about 50 to about 75° C. for a period of 1 to 10 hours ormore.
 18. The method of claim 12 wherein the recovered carbinoxaminetannate is dried by sparging with nitrogen for a period of 1 to 10 hoursor more.
 19. The method of claim 12 wherein the recovered carbinoxaminetannate is milled to provide a free flowing powder.
 20. The method ofclaim 19 wherein the powder has a particle size in the range of about 50to about 200 mesh.